Letrozole, chemically known as 4-[alpha(4-cyanophenyl)-1-(1,2,4-triazoly)-methyl]-benzonitrile, and represented by formula (I),
is a therapeutically and commercially important non-steroidal aromatase inhibitor, which is widely used for adjuvant treatment of hormonally responsible breast cancer in postmenopausal women. Estrogens are produced by the conversion of androgen through the activity of aromatase enzyme, the suppression of estrogen biosynthesis in peripheral tissues and in the cancer tissue itself can therefore be achieved by specifically inhibiting the aromatase enzyme.    1. Bowman et al. were the first to disclose Letrozole in U.S. Pat. No. 4,978,672, and U.S. Pat. No. 5,352,795 and reported two methods for synthesis of Letrozole, the chemistry for Method-1 is summarized in Scheme-I.     The Method-1 for synthesis of Letrozole as disclosed by Bowman et al. in U.S. Pat. No. 4,978,672, and U.S. Pat. No. 5,352,795 and as summarized in Scheme-I, comprises reaction of alpha-bromo-4 tolunitrile or 4-bromomethyl benzonitrile (II) with 1H-1,2,4-triazole (III), in a mixture of chloroform and acetonitrile as solvent at reflux temperature for 15 hours to give 4-[1-(1,2,4-triazolyl)methyl]-benzonitrile (IV), which on reaction with 4-fluorobenzonitrile (VI) in the presence of potassium t-butoxide and in N,N-dimethylformamaide, gives crude Letrozole (I), which is recrystallized from 95% ethanol or a mixture of ether and ethyl acetate to give pure Letrozole (I).
     As would be evident from Examples 9, 25, and 26 of U.S. Pat. No. 4,978,672, and U.S. Pat. No. 5,352,795, in the step reaction of alpha-bromo-4 tolunitrile or 4-bromomethyl benzonitrile (II) with 1H-1,2,4-triazole (III), as per Method-1, Scheme-I, in addition to the desired 4-[1-(1,2,4-triazolyl)methyl]-benzonitrile (IV) an appreciable amount of isomeric 4-[1-(1,3,4-triazolyl)methyl]-benzonitrile (V) is also formed in the reaction, which necessitates separation of the two isomers by column chromatography, subsequent to which the separated pure 4-[1-(1,2,4-triazolyl)methyl]-benzonitrile (IV) is reacted with 4-fluorobenzonitrile (VI) to give Letrozole. Example 25 of U.S. Pat. No. 4,978,672, and U.S. Pat. No. 5,352,795 further report that Letrozole obtained after recrystallization from 95% ethanol has a melting point of 181°-183° C., while Example 26 reports that Letrozole obtained after recrystallization from a mixture of ether and ethyl acetate has a melting point of 184°-185° C.     The major disadvantage and limitation of the Method-1 disclosed in U.S. Pat. No. 4,978,672, and U.S. Pat. No. 5,352,795 is that it leads to formation of appreciable amounts of the unwanted isomer i.e. 4-[1-(1,3,4-triazolyl)methyl]-benzonitrile (V), calling for tedious chromatographic techniques for its separation from the desired isomer i.e. 4-[1-(1,2,4-triazolyl)methyl]-benzonitrile (IV), which is expected to result in considerable loss and low yield of the desired isomer. Such a method, obviously, cannot be expected to be economically or commercially viable. Further, nowhere in the Specifications and Experimental Descriptions of U.S. Pat. No. 4,978,672, and U.S. Pat. No. 5,352,795 there is any mention about the yield and purity of Letrozole obtained by the method described therein. The second method, Method-2, reported by Bowman et al. in U.S. Pat. No. 4,978,672, and U.S. Pat. No. 5,352,795 is summarized in Scheme-II, which comprises of reaction of N-tert.butyl-4-bromo benzamide (1) with n-butyllithium and ethyl formate to give Bis-(4-N-tert.butyl carbamoylphenyl)methanol (2), which on reaction with thionyl chloride gives 4-(alpha-chloro-4′ cyanobenzyl)benzonitrile (3). Reaction of 4-(alpha-chloro-4′cyanobenzyl)benzonitrile (3) with 1H-1,2,4-triazole (III) gives Letrozole (I).
     The major disadvantage and limitation of the Method-2 disclosed in U.S. Pat. No. 4,978,672, and U.S. Pat. No. 5,352,795, as evident from Examples 3, 5 and 28, described therein, is that first of all it utilizes corrosive and hazardous n-butyllithium and thionyl chloride, which require special storage, handling and disposal as well as calls for cryogenic temperatures of −60° C. and higher temperatures of about 160° C., which collectively renders the method unsafe and industrially and commercially not of particular viability. Further, as in the case of Method-1, nowhere in the Specifications and Experimental Descriptions of U.S. Pat. No. 4,978,672, and U.S. Pat. No. 5,352,795 there is any mention about the yield and purity of Letrozole obtained by the Method-2 described therein. Furthermore, the reaction of 4-(alpha-chloro-4′cyanobenzyl)benzonitrile (3) with 1,2,4-triazole (III) would most likely result in formation of the corresponding isomer along with the desired Letrozole, which would involve tedious purification techniques for its separation.     Improvements over the methods disclosed by Bowman et al. in U.S. Pat. No. 4,978,672, and U.S. Pat. No. 5,352,795 are the subject matter of the following reports, viz.    2. Wadhwa et al. in US 2005/0209294 A1, recite a method for synthesis of the intermediate 4-[1-(1,2,4-triazolyl)methyl]-benzonitrile (IV), comprising reaction of alpha-bromo-4 tolunitrile or 4-bromomethyl benzonitrile (II) with a salt of 1H-1,2,4-triazole, preferably an alkali metal salt of 1H-1,2,4-triazole (4), in a suitable solvent at a temperature of between 10° to 15° C., followed by crystallization of the isolated product. The chemistry is summarized in Scheme-III.     Wadhwa et al. in US 2005/0209294 A1, while stating that the method disclosed by Bowman et al. in U.S. Pat. No. 4,978,672, and U.S. Pat. No. 5,352,795 is not selective in that it produces the undesired isomeric 4-[1-(1,3,4-triazolyl)methyl]-benzonitrile (V) in about 50%, which as mentioned hereinbefore requires tedious chromatographic separation techniques for its removal, emphasize that by virtue of utilization of an alkali metal salt of 1H-1,2,4-triazole (4), the desired 4-[1-(1,2,4-triazolyl)methyl]-benzonitrile (IV) is obtained in >96% selectivity, thereby circumventing the utilization of tedious chromatographic techniques for its purification. Wadhwa et al., further state that the said intermediate i.e. 4-[1-(1,2,4-triazolyl)methyl]-benzonitrile (IV), obtained by their method can be converted to Letrozole of US Pharmacopoeial Quality, through conventional procedure.     While the method disclosed by Wadhwa et al. in US 2005/0209294 A1, reportedly affords the intermediate 4-[1-(1,2,4-triazolyl)methyl]-benzonitrile (IV) in >96% selectivity and further, reportedly does away with chromatographic techniques in its isolation, however, the entire Specification and the Experimental Description given in Example-1 therein, is silent about the actual yield and purity of not only the intermediate 4-[1-(1,2,4-triazolyl)methyl]-benzonitrile (IV) but also that of Letrozole obtained by the method. The industrial or commercial viability of the method, therefore, cannot be commented, in view of insufficient disclosure.
    3. Kompella et al. in WO 2005/047269 A1, disclose a method for separation of the Letrozole precursor, 4-[1-(1,2,4-triazolyl)methyl]-benzonitrile (IV) from its isomer, 4-[1-(1,3,4-triazolyl)methyl]-benzonitrile (V), comprising treating a solution of the mixture of the two isomeric compounds (IV) and (V) in dichloromethane or chloroform with isopropylalcohol hydrochloride, followed by addition of isopropyl ether, wherein the hydrochloride salt of the undesired 4-[1-(1,3,4-triazolyl)methyl]-benzonitrile (V) precipitates out, which is removed by filtration. Basification of the filtrate, followed by evaporation of solvent and isolation of the residue from hexane or petroleum ether affords the desired 4-[1-(1,2,4-triazolyl)methyl]-benzonitrile (IV). The method is summarized in Scheme-IV.
     The required isomer is obtained in 47-61% yield and a purity of about 99%.    4. In another variant of the Method-1 of Bowman et al., an improved regiospecific method disclosed by Patel et al. in US 2006/0128775 A1 for synthesis of Letrozole is summarized in Scheme-V.     The method disclosed by Patel et al. in US 2006/0128775 A1 utilizes 4-amino-1,2,4-triazole (5), instead of 1H-1,2,4-triazole (III) or an alkali metal salt of 1H-1,2,4-triazole (4), as utilized by Bowman et al. in U.S. Pat. No. 4,978,672, and U.S. Pat. No. 5,352,795 and Wadhwa et al. in US 2005/0209294 A1 respectively, for reaction with alpha-bromo-4 tolunitrile or 4-bromomethyl benzonitrile (II) to give 4-[(4-amino-1,2,4-triazolium-1-yl)methyl]benzonitrile bromide (6), which on diazotisation leads to the required intermediate, 4-[1-(1,2,4-triazolyl)methyl]-benzonitrile (IV), further reaction of which with 4-fluorobenzonitrile (VI) gives crude Letrozole, which is recrystallized from polar or non-polar solvents to give pure Letrozole (I).     The method of Patel et al. in US 2006/0128775 A1, in the first place provides an elegant regiospecific synthesis of Letrozole in that it like the method of Wadhwa et al. in US 2005/0209294 A1, minimizes the formation of the undesired isomeric 4-[1-(1,3,4-triazolyl)methyl]-benzonitrile (V) and also does away with tedious chromatographic separation techniques.
     The method of Patel et al. in US 2006/0128775 A1, albeit, as evident from Example-1, described therein, reportedly gives Letrozole of 99.90% HPLC purity, however, gives Letrozole of the said purity only in an overall yield of 34%, which renders it of not being an particularly economic process. Secondly, the method comprises of an additional step of deamination of the intermediate compound (6), which in turn calls for a diazotization step, through utilization of sodium nitrite, which is hazardous and explosive, more suitable to small scale preparations rather than industrial manufacture. The method, hence, might not be particularly amenable for industrial scale-up and manufacture.    5. MacDonald et al. in US 2007/0066831 A1, report another variant of the methods disclosed by Bowman et al. in U.S. Pat. No. 4,978,672, and U.S. Pat. No. 5,352,795 and Wadhwa et al. in US 2005/0209294 A1 in that the said method, as summarized in Scheme-VI comprises:            a) Reaction of alpha-bromo-4 tolunitrile or 4-bromomethyl benzonitrile (II) with an alkali metal salt of 1H-1,2,4-triazole (4), in presence of a solvent selected from the group consisting of diemthylacetamide, N-methyl-2-pyrrolididone, or a mixture thereof, at a temperature of about −20° to 0° C. to give 4-[1-(1,2,4-triazolyl)methyl]-benzonitrile (IV);        b) Extracting the impurities form intermediate compound (IV), in a two phase system, comprising an aqueous phase and a water-immiscible phase; and        c) Reacting compound (IV) with 4-fluorobenzonitrile (VI), in presence of a solvent selected from the group consisting of dimethylformamide, diemthylacetamide, N-methyl-2-pyrrolididone, and tetrahydrofuran or a mixture thereof and a base selected from sodium bis(trimethylsilyl)amide, hexyl lithium, butyl lithium, lithium didsopropylamide, alkoxide or mixtures thereof.        
     US 2007/0066831 A1 further, states that the steps (a) and (b) could be combined together resulting in a one-pot synthesis of Letrozole.     In the first place, it might be mentioned herein that the chemistry disclosed by Macdonald et al. in US 2007/0066831 A1 is a nominal variation of the method disclosed by Wadhwa et al. in US 2005/0209294 A1, in that uses specific solvents such as diemthylacetamide, and N-methyl-2-pyrrolididone for formation of compound (IV) and again utilizes the same solvents for obtaining Letrozole from compound (IV), in addition to use of specific lithium containing bases, most of which are hazardous and expensive, requiring special precautions during storage, handling and disposal.    6. In yet another variation, Radhakrishnan et al. in WO 2007/039912 provide a method for synthesis of Letrozole, as summarized in Scheme-VII, which is a one-pot synthesis comprising reaction of compounds (II) and (4) to give compound (IV), which without isolation and on further reaction with compound (VI) gives Letrozole.

The major disadvantage with the method is that is still does not obliterate the use of chromatographic separation/purification of Letrozole.    7. Haider et al. in WO 2007/054964 A2 provide an improvement, as summarized in Scheme-VIII, over Method-1 disclosed by Bowman et al. in U.S. Pat. No. 4,978,672 and U.S. Pat. No. 5,352,795, in that the improvement comprises of selective removal of the isomeric 4-[1-(1,3,4-triazolyl)methyl]-benzonitrile (V), formed in the reaction of compound (II) and (III) in isopropanol as solvent, through a method of extraction, which provides the desired 4-[1-(1,2,4-triazolyl)methyl]-benzonitrile (IV), of >99% purity, and relatively free of the isomeric impurity (V).     The method of extraction, as taught by Haider et al. in WO 2007/054964 A2 comprises repeated extraction of the reaction medium containing mixture of the desired 4-[1-(1,2,4-triazolyl)methyl]-benzonitrile (IV) and the undesired 4-[1-(1,3,4-triazolyl)methyl]-benzonitrile (V) with water and a water-immiscible solvent to afford the pure 4-[1-(1,2,4-triazolyl)methyl]-benzonitrile (IV) in the organic phase, which is then further converted to Letrozole (I) of >99% purity by conventional methods. Haider et al. also teach a process for conversion of the mixture of the desired 4-[1-(1,2,4-triazolyl)methyl]-benzonitrile (IV) and the undesired 4-[1-(1,3,4-triazolyl)methyl]-benzonitrile (V) to Letrozole, from which the isomeric form of Letrozole i.e. Isoletrozole (9) so formed is removed by repeated crystallization to afford Letrozole (I) of >99% purity.     It might be noted that the method of Haider et al., primarily is one for purification of the intermediate 4-[1-(1,2,4-triazolyl)methyl]-benzonitrile (IV) as well as Letrozole (I), for removal of the corresponding isomeric impurities and as such does not provide any inputs for controlling or minimization of the formation of the isomeric 4-[1-(1,3,4-triazolyl)methyl]-benzonitrile (V) in the reaction. Secondly, the method of extraction as well as purification taught by Haider et al. is tedious, comprising multiple extractions, with multiple solvents and this coupled with the fact that it does not provide any improvement in controlling or minimization of the formation of the isomeric 4-[1-(1,3,4-triazolyl)methyl]-benzonitrile (V) in the reaction, leads to significant losses, thereby resulting in rather low yields of Letrozole (I). The method, therefore, is not of commercial significance.
    8. Pizzocaro et al. in WO 2007/090464 A1, a process for preparation of Letrozole (I), as summarized in Scheme-IX, characterized in that it teaches either simultaneous addition of a solution of 4-[1-(1,2,4-triazolyl)methyl]-benzonitrile (IV) and a solution of 4-fluorobenzonitrile (VI) in an aprotic dipolar solvent to a solution of an alkali metal alkoxide in the same aprotic dipolar solvent or addition of an unique solution in an aprotic dipolar solvent comprising of compounds (IV) and (VI) to aprotic dipolar solvent, and reacting at a temperature of between −20° to +40° C.     The method of Pizzocaro et al., in addition to involving adherence to several critical parameters like temperature, flow rate, etc. moreover, does not provide any details of the yields and purity of Letrozole, obtained by the methods described therein.
    9. Srinivas et al. WO 2007/107733 A1 recite a further variation of Method-1 disclosed by et al. in U.S. Pat. No. 4,978,672 and U.S. Pat. No. 5,352,795, for synthesis of Letrozole, substantially free from its isomeric impurity, which is summarized in Scheme-X. The method comprises reacting 4-bromomethylbenzonitrile (II), with 1H 1,2,4-triazole (III) in an organic solvent in presence of cesium carbonate and precipitation of 4-[1-(1,2,4-triazolyl)methyl]-benzonitrile (IV), thus formed from the reaction medium using a suitable organic solvent. The intermediate (IV) is further converted to Letrozole by reaction with 4-fluorobenzonitrile (VI) in presence of an organic solvent and silicon amine, which are lithium, sodium, or potassium disilazanes or monosilazane.     The method utilizes sensitive and expensive silicon compounds like lithium hexamethyldisilazane, which requires highly controlled reaction conditions.
    10. Hasson et al. in US 2007/0112203 A1, provide a method, as summarized in Scheme-XI, for purification of a mixture containing Letrozole (I) and its isomeric impurity i.e. Isoletrozole (IX), which is an extension of Method-2 disclosed by Bowman et al. in U.S. Pat. No. 4,978,672 and U.S. Pat. No. 5,352,795. The method takes advantage of the rapid oxidation of Isoletrozole (9) to 4,4′-dicyclobenzophenone (10), in comparison to Letrozole (I), the oxidized compound (10), being easily separable from Letrozole, can be removed by crystallization, affording pure Letrozole. The Letrozole product, in turn is prepared by Method-2 disclosed by Bowman et al. in U.S. Pat. No. 4,978,672 and U.S. Pat. No. 5,352,795. From the Enabling Disclosures of Hasson et al. in US 2007/0112203 A1, it could be seen that the method of oxidative purification of Letrozole, does not provide the said Letrozole, free of the Isoletrozole impurity (IX), directly and in fact, about 1 to 4% of Isoletrozole (IX) remains in the product, which is further removed by successive crystallizations to provide Letrozole (I) of 99.9% purity.
     It is also noted that Letrozole to some extent also undergoes oxidation, albeit slowly, resulting in formation of additional impurities. Removal of such impurities, coupled with the task of removal of Isoletrozole (IX) and 4,4′-dicyclobenzophenone (10) results in significant yield loss, rendering the method not particularly attractive, economically.    11. Palle et al. in US 2007/0100149 A1, recite an alternate method for synthesis of Letrozole, as summarized in Scheme-XII.
     The method of Palle et al. comprises reacting 4,4′-(hydroxymethylene)bis benzonitrile (12), in turn obtained from 4,4-dibromobenzophenone (11), with p-toluenesulfonyl chloride to give the corresponding p-tolenesulfonate (13), which on reaction with 1H 1,2,4-triazole (III), gives crude Letrozole, which is further purified by successive chromatography and crystallization.     The yield of the p-tolenesulfonate (13), in the key step is only 21%, indicative of formation of large amount of impurities in the said step. Further, the overall yield of Letrozole obtained by the method is only about 14%, which would render the method not viable commercially.    12. Friedman et al. in US 2007/0112202 A1, provide an extension of Method-2 disclosed by Bowman et al. in U.S. Pat. No. 4,978,672 and U.S. Pat. No. 5,352,795, which is summarized in Scheme-XIII.
     US 2007/0112202 A1 reports synthesis of Letrozole by the abovementioned method in 54-56% yield and having a HPLC purity 99.4%, which may not suit Pharmacopoeial standards, which suggests that the product obtained requires further purification, which, incidentally, is acknowledged by Friedman et al., who state that single purification using various solvents does not give Letrozole of acceptable purity, and hence multiple purifications are required to achieve the same. Needless to mention, this would result in significant loss of the precious product. Further, the novelty and inventiveness of the method is in question, since Bowman et al. in U.S. Pat. No. 4,978,672 and U.S. Pat. No. 5,352,795 have disclosed the same chemistry earlier.    13. Agarwal et al. in WO 2007/074474 A1 recite a synthesis of Letrozole, utilizing novel intermediates, the chemistry of which is summarized in Scheme-XIV.
     The method is lengthy and the reported overall yield of Letrozole appears to be only 9-11%.
From the foregoing, it would be abundantly evident that the prior art methods for synthesis of Letrozole and its intermediates suffer from one or more of the following limitations, viz.    i) Formation of significant amounts of the undesired isomeric 4-[1-(1,3,4-triazolyl)methyl]-benzonitrile (V) and Isoletrozole (IX) in the reported methods;    ii) Utilization of tedious chromatographic, extraction, and/or multiple crystallization techniques for separation and removal of the said undesired isomeric impurities;    iii) Utilization of low cryogenic and high reaction temperatures for the key conversion steps;    iv) Involvement of hazardous chemical reactions like diazotization and utilization of hazardous, corrosive, and expensive chemicals and reagents like sodium nitrite, thionyl chloride, n-butyllithium, lithium amides, alkali metal silanes etc.;    v) Lengthy and multiple reaction steps;    vi) Strict adherence to critical reaction conditions and parameters;    vii) Generally moderate to low yields of Letrozole; and    viii) A product, in many instances not conforming to Pharmacopoeial requirements,which collectively render such methods as particularly not having any significant economic, industrial or commercial viability, feasibility, advantage, application or attraction.
Considering the therapeutic and commercial importance of Letrozole, a need, therefore, exists for a method for synthesis of Letrozole, which is simple, convenient, economical, non-hazardous, industrially benign, and, moreover, overcomes the limitations associated with the prior art methods, enumerated hereinbefore.
The present invention is a step forward in this direction and provides a method for synthesis of Letrozole and its intermediates in a purity of ≧99%, which is simple, convenient, economical, and industrially viable, and moreover, overcomes most, if not all the limitations associated with the prior art methods for its synthesis.